Therapeutic light-emitting device

ABSTRACT

An ambulatory device for use in a therapeutic and/or cosmetic treatment, the device comprises an organic light-emitting semiconductor which, in use, covers an area to be treated and emits electromagnetic radiation to cause said therapeutic and/or cosmetic treatment of the area. The light source may be extensive to provide uniform irradiation of the area to be treated and may be pulsed. The device may also include a photopharmaceutical.

RELATED APPLICATION

This application is a continuation of U.S. application Ser. No.10/494,695, filed Oct. 28, 2004, now U.S. Pat. No. 7,824,435, which isthe nationalization of International Application No. PCT/GB2002/005145,filed Nov. 15, 2002.

FIELD OF THE INVENTION

The invention relates to a device for use in therapeutic and/or cosmetictreatment, particularly a treatment which involves exposure of part ofthe body to electromagnetic radiation. The invention also relates tosuch a device and a photo therapeutic agent for use therewith.

BACKGROUND TO THE INVENTION

Light can be used to treat a wide variety of diseases. When light aloneis used to treat a disease, the treatment is referred to asphototherapy. Light may be used in conjunction with a pharmaceutical inwhich case the treatment is called photodynamic therapy (PDT). Thesetherapies can be used to treat a variety of skin and internal diseases.In PDT, a light-sensitive therapeutic agent known as aphotopharmaceutical is supplied externally or internally to an area ofthe body which is to be treated. That area is then exposed to light of asuitable frequency and intensity to activate the photopharmaceutical. Avariety of photopharmaceutical agents are currently available. Forexample there are topical agents such as 5-aminolevulinic acidhydrochloride (Crawford Pharmaceuticals), methylaminolevulinic acid(Metfix®, Photocure). There are also injectable drugs used primarily forinternal malignancies, including Photofin® (from Axcan) and Foscan®(from Biolitech Ltd). Often, the drug is applied in a non-active formthat is metabolised to a light-sensitive photopharmaceutical.

In photodynamic therapy, the primary technique for supplying light tothe photopharmaceutical is to project light of a suitable wavelengthfrom standalone light sources such as lasers or filtered arc lamps.These sources are cumbersome and expensive, and are therefore onlysuitable for use in hospitals. This leads to inconvenience for thepatient, and high cost for the treatment. High light irradiances areneeded in order to treat an acceptable number of patients per day (forthe treatment to be cost effective) and to avoid unduly inconveniencingthe patient.

WO 98/46130 (Chen and Wiscombe) discloses arrays of LEDs for use inphotodynamic therapy. The small LED sources taught therein result inuneven light incident on the patient. Fabrication of arrays iscomplicated because of the large number of connections required. Thedevices shown therein are designed for hospital treatment.

GB 2360461 (Whitehirst) discloses a flexible garment which uses aconventional photodynamic therapy light source to produce light which isthen transmitted through optical fibres. As such light sources areheavy, the device is not ambulatory and is limited to hospital use.

U.S. Pat. No. 5,698,866 (Doiron et al) discloses a light source usingover-driven inorganic LEDs. The resulting light output is not even. Aheat-sinking mechanism is required, and the device is suitable only forhospital treatment.

WO 93/21842 (Bower et al) disclose light sources using inorganic LEDs.Although transportable, the device is not suitable for ambulatory use bya patient at home and clinical treatment is envisaged.

A further problem with existing approaches is that it can be difficultto achieve uniform illumination with such sources, especially on curvedbody parts.

SUMMARY OF THE INVENTION

According to a first aspect of the present invention there is providedan ambulatory device for use in a therapeutic and/or cosmetic treatment,the device comprising an organic light-emitting semiconductor which, inuse, covers an area to be treated and emits electromagnetic radiation tocause said treatment of the area.

Preferably, the device is for use in the treatment of a human or animalpatient by photodynamic therapy.

Preferably, the organic semiconductor is operable to emit light in thewavelength range of 300-900 nm.

Organic semiconductors are lightweight, and can readily be powered byportable low voltage power supplies, such as batteries, forming atotally self-contained portable unit. Indeed, the photo-therapeuticdevice may to advantage include a power supply for operating the organiclight-emitting semiconductor. The device is sufficiently portable toenable ambulatory treatment i.e. treatment in which the patient can movearound freely. It can be subsequently removed in the patient's own time,so that treatment could take place at home or at work. This givesgreater convenience and lower cost (from avoiding either an out-patientor in-patient stay in hospital). It also means that lower light levelscan be used since exposure can occur for a longer period of time. Thisovercomes a problem of pain induced in some patients by the highirradiances from conventional sources used in hospitals. In additionlower irradiance is more effective in PDT due to reduction of the extentof photobleaching of the photopharmaceutical.

Preferably, the light emitting semiconductor provides an extensive lightemitting area. In contrast to point sources (such as inorganic lightemitting diodes) a more even light output is thereby produced. The lightemitting semiconductor preferably has an extent of at least 1 cm² andpreferably is in the range 3 cm² (for small lesions) through to 100 cm²although semiconductors as large as 400 cm² might be used for a head.Preferably also, the light emitting surface of the semiconductor iscontinuous. The light emitting surface may conveniently be square, e.g.1 cm×1 cm, 2 cm×2 cm, 5 cm×5 cm, 10 cm×10 cm, or circular.

The device may be planar, or may be curved in advance or in situ toconform to the surface of the area to be exposed to light from theorganic light-emitting semiconductor.

Preferably, the device is flexible so as to be capable of being formedinto any of a number of possible different configurations in advance orextemporaneously to the shape of the body part to which it is to beapplied. The device may be disposable, i.e. used to deliver onetreatment and then thrown away.

The device may be used as a stent, for example a tube of 1.25-2.25 cmradius of say 10-12 cm length for use inside the oesophagus.

Preferably, the device includes a transparent or translucent substratelayer of preferably even thickness which additionally functions as asupport layer for the organic light-emitting semiconductor. The supportlayer can also act as a barrier layer and be selected to prevent oxygenand/or moisture from penetrating the organic light-emittingsemiconductor and is preferably glass. A glass/plastic laminatestructure may also be used and there may be a further barrier layeroverlying the organic light-emitting semiconductor.

The device conveniently includes an adhesive surface for attaching thedevice to a patient.

For planar devices, the preferred substrate is glass. However, asorganic semiconductors can be flexible, flexible devices can be madeusing a combination of flexible components (including the substrate).Indium tin oxide (ITO) coated polyester is a suitable substrate thoughits inferior barrier properties mean that devices using this substraterequire storage (or packaging) in an inert atmosphere. Another substratethat can be used is a laminate of alternate layers of plastic and asuitable glass. Such laminates or indeed a single glass layer ifsufficiently thin, can display a suitable elastic quality to be useablein a flexible device.

Preferably, the organic light-emitting semiconductor is an organiclight-emitting diode. Preferably the light-emitting diode comprises alayer of the conducting polymer PEDOT/PSS which assists with holeinjection into the light-emitting layer, reducing the operating voltageof the device. The light-emitting diode, may comprise an organiclight-emitting layer of OC₁C₁₀-PPV (see FIG. 2) which can readily bemade into films by spin-coating and gives orange-red light emission. Thelight-emitting semiconductor may be based on small organic molecules,light-emitting polymers, light-emitting dendrimers or other organiclight-emitting semiconductor materials.

A multilayer organic semiconductor structure is only one option and asingle organic semiconductor layer can fulfill the required functions,namely that electrons and holes are injected at opposite contacts,transported in the layer where capture of opposite charges then forms anexcited state which can then emit light. A single semiconducting layerdevice can be used with a further layer of the conducting polymer PEDOTon an indium tin oxide layer.

The devices may be provided with a photochemical and/or aphotopharmaceutical preparation present. This may be in the form of agel, ointment or cream. Alternatively, or as well, the device may beprovided with a thin film impregnated with the photopharmaceutical.Typically, the photopharmaceutical preparation is provided as a layer incontact with the light source. Provided that the photopharmaceuticalpreparation is transparent or sufficiently translucent for the frequencyof stimulating light, the resulting device can be readily appliedwithout a separate step of applying the photopharmaceutical to apatient. Creams which would scatter the light may nevertheless be usedif they are absorbed before the light source is switched on. Aphotopharmaceutical layer may be covered by a peelable release medium,such as a silicone-backed sheet. The photopharmaceutical preparation maycomprise an inactive compound which is metabolised in vivo to an activecompound. Delivery of the photopharmaceutical can be assisted byiontophoresis.

The output of light from the organic light-emitting semiconductor may bepulsed and an electronic control circuit or microprocessor may beprovided to control this pulsing and/or other aspects of device functionsuch as duration of exposure(s) of the area to be treated and theintensity of emitted light. Pulsed devices may be provided with apreparation of a photochemical and/or a photopharmaceutical substancewhich is photobleachable or which is metabolised in vivo to aphotobleachable chemical species.

The output of the semiconductor may take the form of a train of pulses,preferably in which the duration of the pulses is substantially the sameas the interval between successive pulses. The period of the pulse trainmay, for example, be in the range of 20 ms to 2000 s, depending on thephotobleaching characteristics of said substance.

According to a second aspect of the present invention there is providedan ambulatory device for use in therapeutic treatment (preferably byphotodynamic therapy), the device comprising a light-emitting layer,wherein the device including said layer is flexible so that, whenapplied to a curved part of a body, the light-emitting layer conforms tothe shape of the surface of the area to be treated.

Preferably, the device includes attachment means comprising an adhesivesurface to enable the device to be attached to a patient.

Further preferred features correspond to the first aspect above.

According to a third aspect of the present invention there is providedan ambulatory device according to the first or second aspect above and aphoto-therapeutic chemical, preferably a photopharmaceutical agent foruse in photodynamic therapy, for use with the device.

The pulsing of the light used to activate a phototherapeutic chemicalcan also be advantageous in rigid devices or, devices having types oflight source, for example a laser, other than organic semi conductors.

Thus, according to a further aspect of the invention, there is providedan ambulatory device for use in photodynamic therapy, the devicecomprising an electromagnetic radiation source, attachment means forattaching the electromagnetic radiation source to a patient and controlmeans for activating and deactivating the source to cause the latter toemit a train of light pulses for activating a photodynamic chemical,whilst reducing the effects of photo bleaching on the chemical.

Preferably, the ambulatory device is provided with a photochemicaland/or a photopharmaceutical preparation present. Preferred features ofthe preparation and its delivery are as above. In particular, thephotochemical and/or photopharmaceutical may be photobleachable or maybe metabolised in vivo to a photobleachable chemical species.

The means for activating and deactivating the source may control otheraspects of device function such as duration of exposure(s) of the areato be treated and the intensity of emitted light.

The control means may to advantage be operable to cover the source toemit a pulse train having any one or more of the preferred features ofthe pulse train produced by a device in accordance with the first aspectof the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

An embodiment of the present invention will now be described, by way ofexample only, with reference to the following figures in which:

FIG. 1 is a schematic cross-section through a therapeutic deviceaccording to the present invention;

FIG. 2 is the chemical structure of the polymer OC₁C₁₀-PPV used in thedevice; and

FIG. 3 is a graph of the spectrum of light emitted by a therapeuticdevice including OC₁C₁₀-PPV as the light emitting layer;

FIGS. 4( a) through 4(d) are graphs of the current voltagecharacteristics, the light output-voltage characteristics; the lightoutput-current density characteristics and the external quantumefficiency-voltage characteristics respectively of the device of FIG. 3;

FIG. 5 is a graph of the spectrum of light emitted by a device in whichthe light-emitting layer is poly(dihexyfluorene);

FIG. 6 is a cicuit-diagram of a 108 gram power source for use with theinvention; and

FIGS. 7( a) through (c) illustrate the light output from OC₁C₁₀-PPVdevices operated with pulses of period (a) 20 ms, (b) 200 ms, (c) 2000ms.

DETAILED DESCRIPTION

A photo-therapeutic device shown generally as 1 is connected to by wayof leads 3 to a battery power supply 2. The photo-therapeutic devicecomprises a light-generating element shown generally as 10 which ispowered by the power supply 2.

The light generating element 10 comprises an organic light-emittingdiode using a layer of the polymer OC₁C₁₀-PPV as the light-emittinglayer 14 in between suitable contacts. The hole injecting contactconsists of an indium tin oxide coated glass substrate (11 and 12)coated with a layer 13 of the conducting polymerpoly(3,4-ethylenedioxyhiophene) doped with polystyrenesulphonate(PEDOT/PSS). The electron injecting contact is a layer of calcium 15which is chosen because of its low work function and is capped withaluminium 16. Light emission occurs when a current is passed between thecontacts.

The lower electrode layer 12 and the glass substrate 11 are transparent.Glass is a suitable material as it also has the properties of beingtransparent and both oxygen and water-proof. An upper support layer 18,also formed from glass, acts as a barrier to water and oxygen, providesadditional mechanical support and is attached to the upper electrodelayer 16 and is sealed by means of an epoxy layer 17. Adhesive tape 19extends over the light-generating element 10 and beyond the element 10to provide adhesive surfaces 22 and 24 for attaching the device to apatient. Prior to attachment, these surfaces are protected by removableplastics films 20 and 21.

FIG. 2 illustrates the chemical structure of OC₁C₁₀-PPV. The mainfeatures are a conjugated backbone enabling charge transport, and givingan energy gap in the visible region of the spectrum. The alkoxysubstituents confer solubility, and thin films of the polymer canreadily be prepared by spin-coating.

Light is passed to the patient's skin from the light-generating element10 through the transparent substrate 11. In a first example, thetransparent lower support layer 11 and upper support layer 18 are planarand rigid, giving mechanical strength. Batteries are a suitable powersupply with control electronics incorporating controls for time ofexposure, including the possibility of a delayed start to allow aphotopharmaceutical to be metabolised into its photoactive form.Controls for brightness and pulsing may be included.

An example of a method of making the device will now be described. Theindium tin oxide coated glass substrate 11 and 12 (Merck 20Ω/□) wascleaned by ultrasound in acetone followed by propan-2-ol (10 minutes ofeach). After drying, and an optional step of exposure to an oxygenplasma, a layer of the conducting polymer PEDOT/PSS (Bayer Baytron VPA14083) was spin-coated from aqueous solution at a spin speed of 2200rpm for 1 minute. The film was baked at 80° C. for 3 minutes. Thelight-emitting polymer OC₁C₁₀-PPV (see FIG. 2) was then deposited byspin-coating a solution of 5 mg/ml of the polymer in chlorobenzene at aspeed of 1750 rpm. The resulting film was in the region of 100 nm thick.This and subsequent fabrication steps were carried out in the inertatmosphere of a nitrogen glove box. The structure was loaded into anevaporator (Edwards 306) to allow the deposition of the top contact. Athin layer of calcium (25 nm) was evaporated thermally, followed by athicker layer (140 nm) of aluminium. The pressure during theevaporations was 1.5-5×10 mbar, and the two metals were depositedwithout breaking the vacuum. The above layers were then encapsulated bya glass layer 18 attached with epoxy resin 7. Adhesive tape 19 wasapplied and covered by a plastics films 20 and 21.

In order to test the device it was connected to a power supply (Keithley2400 source measure unit). The light-emitting area was 1 cm². When avoltage (in the range 3-10 V) was applied, orange light emission throughthe substrate was observed. The device generated an irradiance in therange 0-10 mW/cm² which is considerably lower than those generated byconventional sources, such as lasers and filtered lamps, as thesetypically generate irradiances in the region 75-150 mW/cm².Alternatively the device could be driven by applying a current, and theintensity of the light was approximately proportional to the currentsupplied. The spectrum of the light emitted is shown in FIG. 3. Thedevice is applied to skin by removing the plastic films 20 and 21 andallowing the adhesive tape to stick to the skin.

The current-voltage, light output-voltage, light output-current densitycharacteristics and the external quantum efficiency (EQE)-voltagecharacteristics are shown in the form of graphs in FIGS. 4( a) through4(d).

A similar device was made using poly (dihexylfluorene) as thelight-emitting layers, giving emission in the blue-green region of thespectrum, as shown in the graph of FIG. 5.

The 1 cm×1 cm device weighed 1.26 g and was used with a 108 g batterypower source, providing a light-weight ambulatory device. The powersource consists of 4 conventional AA batteries and the simple currentregulating circuit of FIG. 6. The 108 g power source also providessuitable power output for a 2 cm×2 cm device. A 200 g battery pack canpower a 5 cm×5 cm device.

The device could be used for skin and internal disorders. A range ofpre-malignant, malignant and inflammatory diseases would be the target.Examples of pre-malignant skin disease are Bowen's disease, solarkeratosis, arsenical keratosis, Paget's disease and radiodermatitis.Malignant diseases include all types of basal cell carcinomas, squamouscell carcinomas, secondary metastases, cutaneous T-cell lymphomas.Inflammatory skin diseases include all types of dermatitis andpsoriasis.

Further diseases that are potential targets are a range ofpre-malignant, malignant and non-cutaneous disorders such as primary andmetastatic tumours, as well as inflammatory disorders, eg connectivetissue disease, all types of arthritis, inflammatory bowel disease.

Photopharmaceuticals can undergo reversible light-induced change,especially at high irradiances, which reduces the effectiveness ofsubsequent treatment—an effect referred to as photobleaching.

As reversible photobleaching of the photopharmaceutical is known toresult in reduced penetration of light into the target tissue, amodified version of this device has a facility automatically to switchon and off the irradiation so delivering the desired dose, limitingphotobleaching and enabling fresh uptake/metabolism of thephotopharmaceutical within remaining viable target cells. This wouldhave the clear benefit of increasing therapeutic effectiveness. Thepulse trains constituting the light-output of such pulsed devices(periods 20, 200, 2000 ms) are shown in FIG. 7. Pulsed operation with aperiod of 20 s, 200 s and 2000 s was also demonstrated and longerperiods can be envisaged. Pulse shape and duration can readily beoptimised for a particular application by experiment and calculation. Inthe examples shown, each period is constituted be a pulse and aninterval between it and the next pulse, the interval being the same asthe duration of the pulse.

The light-emitting device would be used either on its own as a simplelight source applied to the skin or via an internal appliance such as anasogastric tube, chest drain or stent. For skin lesion management, thedevice would be used either alone or in combination with thephotopharmaceutical in a translucent base such as a gel or ointmentapplied as a single dressing. Creams which scatter light may be used ifthey are sufficiently absorbed into the skin. A range ofphotopharmaceutical agents are currently available and it is expectedthat new agents of greater specificity and phototoxic effect willemerge. Examples of topical agents presently used include5-aminolevulinic acid hydrochloride (Crawford Pharmaceuticals),methylaminolevulinc acid (Metfix, Photocure). Injectable drugs used inthe main for internal malignancies, are two in number, Photofrin (Axcan)and Foscan (Biolitech).

A second example of the invention consists of a flexible device. Herethe substrate consists of a polyester film in place of glass layer 11.Layers 12 to 16 are as for the first example. Epoxy layer 17 is verythin, and layer 18 is polyester. The inferior barrier properties of theplastic layers 11 and 18 mean that this device must be stored (orpackaged) in an inert atmosphere such as dry nitrogen, but can beoperated in air.

In this example, the element 10 is able to flex to fit the shape of apart of the patient's body, such as the arm. In this example, thetransparent support layer and upper support layer are made from a thinflexible glass, a plastic/glass laminate or indium tin (ITO) coatedpolyester. The latter would be stored in an inert atmosphere until it isused.

Further alterations and amendments can be made by one skilled in the artwithin the scope of the invention herein disclosed. For example, theinvention could be used, with a photopharmaceutical, in a cosmetictreatment, and/or have veterinary, as well as medical, applications.

The invention claimed is:
 1. An ambulatory device for use in photodynamic therapy, the device comprising an electromagnetic radiation source, attachment means for attaching the electromagnetic radiation source to a patient and control means for activating and deactivating the source to cause the latter to emit a succession of light pulses for activating a photodynamic chemical, whilst reducing the effects of photobleaching on the chemical, wherein the succession of light pulses has a period in the range of 20 ms to 2000 s and wherein the electromagnetic radiation source is a single organic light-emitting semiconductor, and wherein the ambulatory device is operated from a battery pack weighing less than 200 g, and wherein the photodynamic chemical is in the form of a photopharmaceutical in a translucent base or a cream which scatters light and which is absorbed into the skin.
 2. An ambulatory device according to claim 1, wherein an electronic control circuit or microprocessor is provided to control the pulsing, duration of exposure(s) of an area to be treated and/or the intensity of emitted light.
 3. An ambulatory device according to claim 1, wherein the photodynamic chemical is a photochemical and/or a photopharmaceutical substance which is photobleachable or which is metabolised in vivo to a photobleachable chemical species.
 4. An ambulatory device according to claim 1, wherein the succession of light pulses forms a train of pulses and wherein the duration of the pulses is substantially the same as the interval between successive pulses.
 5. An ambulatory device accordingly to claim 1, wherein the period of the succession of light pulses depends on the photobleaching characteristics of the photodynamic chemical.
 6. An ambulatory device according to claim 1, wherein the electromagnetic radiation source is a laser or an organic light-emitting semiconductor.
 7. An ambulatory device according to claim 1 for use in the treatment of a human or animal patient by photodynamic therapy.
 8. An ambulatory device according to claim 1 which is adapted to conform to the surface of the area to be exposed to light.
 9. An ambulatory device according to claim 1 which is flexible so as to be capable of being formed into any of a number of possible different configurations in advance or extemporaneously to the shape of the body part to which it is to be applied.
 10. An ambulatory device according to claim 1 which includes a transparent or translucent substrate layer.
 11. An ambulatory device according to claim 1 which includes an adhesive surface for attaching the device to a patient.
 12. An ambulatory device according to claim 1, electromagnetic radiation source wherein the organic light-emitting semiconductor is an organic light-emitting diode.
 13. An ambulatory device according to claim 1, wherein the period selected from the group of at least 20 ms, at least 200 ms, at least 2 s, at least 20 s, at least 200 s or at least 2000 s.
 14. An ambulatory device according to claim 1 further comprising a photopharmaceutical preparation.
 15. An ambulatory device as claimed in claim 14 wherein the photopharmaceutical preparation comprises an inactive compound which is metabolised in vivo to an active compound. 